The present invention relates to novel naphthalene derivatives. In particular, it relates to novel naphthalene derivatives useful for reducing blood sugar and blood lipid levels.
Diabetes is a compound disease caused by hyperglycemia which results from dysfunction of insulin which reduces blood sugar level. Diabetes can be classified into several types based on etiology. Among others, two types of diabetes are most important, one of which is insulin-dependent diabetes mellitus (type I diabetes) which is caused by insulin deficiency and requires insulin supply for the treatment of the disease, and noninsulin-dependent diabetes mellitus (type II diabetes) which is caused by abnormalities of insulin receptors or sugar transporting carriers in spite of sufficient production of insulin.
At present, the treatment of noninsulin-dependent diabetes mellitus is mainly carried out by a combination of ergotherapy, alimentary therapy, and oral administration of anti-hyperglycemic agents, and for more severe conditions, insulin preparations are used. As anti-hyperglycemic agents for oral administration there are used sulfonylureas (for example, tolbutamide, acetohexamide, tolazamide, glibenclamide, etc.) and biguanides. However, biguanides are scarcely used because of their side effects such as lactic acidosis and the like. On the other hand, sulfonylureas show potent anti-hyperglycemic activity but can sometimes induce hypoglycemia. Accordingly, sulfonylureas must be used very carefully. In addition, a phenomenon knows as "secondary failure" is seen during the use of sulfonylureas for a long period of time, which means gradual decrease of effectiveness.
Although a variety of new anti-hyperglycemic agents having less side effects than sulfonylureas have been currently developed, most of them have not been put into practical use due to their insufficient activities and side effects.
In recent years, insulin-resistance ameriolating agents have attracted the attention of people concerned, which reduce blood sugar level by ameriolating insulin-resistance in peripheral tissues, which is one of the causes of noninsulin-dependent diabetes mellitus. However, conventional insulin-resistance ameriolating agents are unsatisfactory because of their insufficient desirable effect and undersirable side effects, and it has long been desired to develop new agents which have more powerful effect and less side effects.
Japanese patent publication (Kokai) No. 48471/1984 discloses thiazolidine derivatives which reduce blood sugar and triglyceride levels in blood plasma. The derivatives are represented by the following formula: ##STR3## wherein each of L.sup.1 and L.sup.2 is defined as hydrogen when R.sup.a is a suitably substituted phenyl, and R.sup.b is a bond or a lower alkylene.
Japanese patent publication (Kokai) No. 267580/1988 discloses thiazolidinedione derivatives having an ability of reducing blood sugar and blood lipid levels, which are represented by the following formula: ##STR4##
Further, U.S. Pat. No. 4,703,052 describes thiazolidinedione derivatives having an ability of reducing blood sugar and blood lipid levels, which are represented by the following formula: ##STR5## wherein the dotted line is an arbitrary bond; R.sup.c is hydrogen, methyl or ethyl, X.sup.a is O, S, SO, SO.sub.2, CH.sub.2, CO, CHOH or NH.sup.h (R.sup.h is hydrogen) or acyl group; R.sup.d, R.sup.e R.sup.f are hydrogen or methyl; and R.sup.g is a substituted phenyl, benzyl, phenethyl or styryl.
British patent No. 8713861 discloses thiazolidinedione derivatives having an ability of reducing blood sugar and blood lipid levels, which are represented by the following formula: ##STR6## wherein A.sup.o represents nitrogen or R.sup.t --C(=)-- moietry, R.sup.k represents R.sup.t --Y.sup.a --Z wherein R.sup.t represents a substituted or a unsubstituted phenyl, pyridyl or oxazolyl group, Y.sup.a represents --(CH.sub.2)n.sup.a --(n.sup.a stands for an integer of 0 to 6) and Z represents --CH.sub.2 --, --CH(OH)-- or --CO--; each of R.sup.i and R.sup.j represents hydrogen or R.sup.i and R.sup.j combine together to form a bond; A represents a residue of a benzene ring; and X.sup.b represents O or S).
Further, Japanese patent publication (Kokai) No. 56675/1989 discloses thiazolidinedione derivatives having an ability of reducing blood sugar level, which are represented by the following formula: ##STR7## wherein R.sup.m represents phenyl, naphthyl, cycloalkyl or heterocycle, all of which may be substituted; Alk represents a single bond, lower alkenylene, lower alkynylene, or lower alkylene which may be substituted; and the dotted line represents a bond which may be a double bond.
As described above, among thiazolidinedione derivatives having an ability of reducing blood sugar and blood lipid lebels, and which have been disclosed so far, there has been no compound wherein the aromatic ring moiety to which 5-(2,4-thiazolidinedione)-methyl group or 5-(2,4-thiazolidinedione)-methylene group is attached has a naphthalene structure.
On the other hand, U.S. Pat. No. 4,997,948 issued to Zask et al. discloses naphthalenylsulfonyl thiazolidinedione derivatives having an ability of reducing blood sugar level, which are represented by the following formula: ##STR8## wherein R.sup.n represents hydrogen, bromine, chlorine, trifluoromethyl or difluoroethyl; R.sup.o represents hydrogen, hydroxyl, methoxyl or ethoxyl when R.sup.p represents hydrogen, or both R.sup.o and R.sup.p represent methoxycarbonyloxyl or ethoxycarbonyloxyl; m.sup.a represent 0 or 2; and n.sup.b represents 0 or 1. However, their effect of reducing blood sugar can not be said to be sufficient.
Further, Zask et al., J. Med. Chem., 33 (5): 1418-1423 (1990) discloses thiasolidine derivatives showing the effect of reducing blood sugar level, which are represented by the following formula: ##STR9## but such compounds can not be said to have sufficient effect on reducing blood sugar level.
Keath et al., J. Med. Chem., 32 (1): 11-13 (1989) discloses tetrazole derivatives showing an effect of reducing blood sugar level, which are represents by the following formula: ##STR10## wherein R.sup.n represents C.sub.1 -C.sub.10 perfluoroalkyl.
European patent publication No. 393941 discloses naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole-2-oxides showing the blood sugar level reducing effect, which are represented by the following formula: ##STR11## wherein R.sup.o and R.sup.p represent independently hydrogen, lower alkyl having 1 to 6 carbon atoms, lower alkoxyl having 1 to 6 carbon atoms, halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro or halogen-substituted benzyloxyl; and n represents 0 to 4.
Further, European patent publication No. 343643 discloses a compound represented by the following formula: ##STR12## wherein Y.sup.b represents an oxygen atom or sulfur atom, which are compounds having a structure similar to that of the compounds of the present invention. They are different from the compounds of the present invention in the substituents attached to the naphthalene ring. In addition, the above publication describes that the object is to use the compounds for treatment of allergy or inflammation and it refers to nothing for the reduction of the blood sugar and blood lipid levels, which is the object of the present invention.